Another novel agent, a monoclonal antibody against a human protein apparently expressed from what used to be called "junk DNA" in the human genome, is also being tested among patients with MS.

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TUESDAY, March 26, 2013 (MedPage Today) —
A host of upcoming and recently approved multiple sclerosis drugs are
on the horizon. Here's a look at four of them, plus a peek at an
entirely novel treatment approach.

For physicians interested in the newest MS therapies, last
week's meeting of the American Academy of Neurology offered a feast of
well-funded research on investigational agents including alemtuzumab
(Lemtrada), dimethyl fumarate (BG-12), ocrelizumab, and laquinimod.

Primary analyses of the pivotal studies for the
investigational agents had all been reported previously, either in
meeting presentations or in detailed announcements from the drugs'
manufacturers. Presentations at the meeting therefore focused on
longer-term efficacy and safety data.

One novel agent -- a monoclonal antibody against a human
protein -- aims at testing a tantalizing MS disease hypothesis.

Alemtuzumab, for which an FDA approval decision is slated for
this fall, has been closely watched in the MS field because it is
administered in two courses 1 year apart, with additional dosing only
if patients show significant clinical worsening.

One of the two phase III studies, CARE-MS I, had enrolled
treatment-naive patients and the other, CARE-MS II, involved patients
who were failing on other drugs for relapsing-remitting MS. In both
studies, the comparator treatment was standard interferon-beta-1a
(Rebif).

After completion of the 2-year randomized phases, patients
initially receiving alemtuzumab who chose to remain in the extension
study were monitored for relapse or new MRI lesion activity, in which
case they could receive another course of therapy.

Edward Fox, MD, of Central Texas Neurology Consultants in
Round Rock, Texas, told AAN attendees that nearly all patients
completing the randomized phases agreed to enter the extension study.
Patients in the original interferon arms had not yet completed the
first year of post-treatment monitoring, so he reported extension
results only for patients initially assigned to alemtuzumab.

Relapse rates in these patients during the first year of the
extension -- that is, the second full year after their last alemtuzumab
dose -- averaged 0.24 and 0.25 in the CARE-MS I and CARE-MS II
alemtuzumab arms, respectively. Corresponding retreatment rates during
the extension were 18% and 20%, Fox reported.

Autoimmune reactions have been the most serious adverse
effects seen previously with alemtuzumab, and this was confirmed in the
extension. Nearly 20% of patients developed autoimmune thyroid
abnormalities during the extension, for a cumulative 3-year rate of 30%.

However, Fox told MedPage Today that the
condition had been manageable, with patients receiving standard
treatments for hyperthyroidism. He said his impression was that
patients did not find it a severe burden, and it did not appear to
compromise the drug's effectiveness against MS.

More serious conditions including autoimmune thrombocytopenia
and nephropathy were much rarer, with cumulative 3-year incidence rates
of 1.3% and 0.3%, respectively.

Fox said strict monitoring and patient education with respect
to autoimmune effects would be critical to keeping alemtuzumab as a
relatively safe treatment.

Dimethyl Fumarate

An oral drug, dimethyl fumarate has drawn attention because of
very impressive reductions in relapse rates, MRI activity, and
disability progression in its controlled phase III trials in
relapsing-remitting MS.

In a platform presentation, Robert Fox, MD, of the Cleveland
Clinic, reported on a secondary analysis of the two pivotal studies,
dubbed DEFINE and CONFIRM, focusing on the time course of the drug's
efficacy effect.

Given twice daily at 240 mg, dimethyl fumarate demonstrated a
significant reduction in relapse rate relative to placebo within the
first 10 weeks of treatment, Fox said.

Also, new and/or enlarging T2 lesions seen in MRI scans were
lower by 72% within 24 weeks compared with placebo. This suppression of
MRI disease activity was maintained through week 96 in the pooled data,
with a reduction of 82% during treatment weeks 48 to 96.

Gadolinium-enhancing lesions were reduced even more -- by 88%
during the first 24 weeks and by 83% from weeks 48 to 96, Fox reported.

The drug's safety and tolerability were addressed separately
in a poster presentation by Fox and colleagues, who reported early
results from an extension study called ENDORSE, in which participants
in the pivotal studies who have chosen continued open-label treatment
are being followed for up to 5 years.

In the poster report, nearly 1,600 patients had completed 6
months in the extension, with 1-year data on about 1,100. Some 40% of
these had switched to dimethyl fumarate from placebo or open-label
glatiramer acetate, which also served as a comparator in the pivotal
studies.

Patients who had previously taken dimethyl fumarate in the
randomized phases showed few adverse effects during the extension,
although that was expected since patients with tolerability problems
would have been less likely to continue with the drug.

Among patients who switched to dimethyl fumarate in the
extension, a total of 15% discontinued because of adverse effects.
Gastrointestinal complaints accounted for the bulk of these, with about
one-quarter of discontinuations attributed to flushing or pruritus.

As in the controlled phases, mild elevations in liver enzymes
were common, but rates higher than three times the upper limit of
normal were seen only in about 6% of patients who switched to dimethyl
fumarate. Renal events were seen in about 10% to 12% of all patients in
the extension, including those who had taken the drug in the randomized
phases.

Separately, dimethyl fumarate's developer, Biogen Idec, said
last week that the drug had been endorsed by the European Union's
Committee for Medicinal Products for Human Use, paving the way for
final European approval. The firm expects the FDA to issue an approval
decision within days. Biogen Idec has settled on Tecfidera as its brand
name for the drug.

Ocrelizumab

This injectable biologic drug, which targets the same
cell-surface protein on B cells as rituximab (Rituxan), was highlighted
in a platform presentation by Stephen Hauser, MD, of the University of
California San Francisco.

He reported 144-week results from a randomized phase II study
in 218 patients with relapsing-remitting MS. The trial began with a
24-week phase in which patients were assigned to one of two ocrelizumab
doses, placebo, or interferon-beta. Data from that phase were previously reported.

Patients in the two ocrelizumab arms continued, while those in
the comparator groups switched to the lower, 600 mg/24 weeks
ocrelizumab dose (the higher dose was 1,000 mg/24 weeks) through week
96. Treatment was then stopped and patients were followed off-drug for
48 more weeks.

Hauser reported that 168 patients of the original 218 remained
in the study for the full 144 weeks, with six stopping during the
treatment phase for insufficient response and eight because of adverse
effects, including one death.

The trial's primary endpoint was the number of
gadolinium-enhancing MRI lesions. From baseline mean levels of 1.5 to 4
in the four original treatment arms, these lesion counts were knocked
down to near zero by week 12 in the two ocrelizumab arms and all the
way to zero by week 48. They remained at zero through week 120 before
rebounding to a mean of about 0.3 at the final MRI scan.

Adjusted annualized relapse rates during weeks 96-144 were
0.116 in the original placebo group, 0.082 in the original low-dose
ocrelizumab group, 0.352 in the original high-dose group, and 0.076 in
the original interferon group.

The lone death in the study involved a patient who developed a
systemic inflammatory response syndrome at week 12 and died 2 weeks
later.

Other serious adverse events -- a total of 27 during treatment
and seven during post-treatment follow-up -- included infections, two
cases of seizure, inflammatory episodes in various organs, and two
cases of suicidal ideation or attempt.

None of the infections involved opportunistic pathogens, and
the overall safety profile was consistent with earlier reports, Hauser
said.

Three phase III trials are now under way with results expected
late in 2015, he said.

Laquinimod

As in the trials for the other drugs, patients in a phase III
trial of laquinimod -- an orally active immune modulator -- were
invited to continue in an open-label extension. Results from the first
year were reported by Giancarlo Comi, MD, of the University Vita-Salute
San Raffaele in Milan, Italy.

In the extension, primary endpoints were safety and disability
progression in patients continuing on laquinimod versus those switching
to the drug from placebo.

Of the 864 patients completing the 2-year randomized phase
(about 80% of the original enrollment), all but 25 agreed to
participate in the extension, planned to last for 18 months.

Cumulative 3-year relapse rates were higher for patients in
the original placebo group compared with those randomized to
laquinimod, Comi reported. But annualized relapse rates in the former
placebo patients during the first year of the extension were similar to
those seen in the laquinimod group during their second year on therapy
(0.23 versus 0.24, respectively).

Rates of disability progression were also similar in the two
groups during the extension. In the patients who remained on the drug
for the full 3 years, just under 15% had confirmed 6-month disability
progression by the end of year three, Comi said.

Adverse events were less frequent in the extension than in the
randomized phase, even among those patients switching from placebo. The
most common events were headache, back pain, urinary tract infection,
diarrhea, cough, abdominal pain, and liver enzyme elevations.

Most such events were mild. During the extension, about 1.5%
of patients showed liver enzyme levels more than three times the upper
limit of normal.

Five deaths occurred in the study, including two in the
extension phase. Two were suicides; the others were an acute coronary
event, a train accident, and complications from pneumonia.

Overall, Comi said, the safety profile seen in earlier studies
was confirmed in the extension, with many types of events becoming less
common over time with continued treatment.

An Entirely Novel Approach

Another drug study reported here could revolutionize thinking
about MS altogether if the agent proves to be beneficial in larger
trials.

GeNeuro in Geneva, Switzerland, has developed a monoclonal
antibody against a human protein apparently expressed from what used to
be called "junk DNA" in the human genome.

Addressing attendees at the AAN meeting, the company's CEO,
François Curtin, MD, MPhil, MBA, noted that about 8% of the human
genome is believed to be "human endogenous retrovirus" (HERV) sequences
-- in effect, fossilized remnants of retroviruses that once infected
human ancestors.

Most HERV sequences are incapable of expression, but "some
elements are active," Curtin said.

One such element produces a protein, he said, that appears to
be a viral envelope protein and that has been associated with MS. It
has been dubbed MSRV-Env and has been found on the surface of monocytes
and microglia known to be active in the disease, as well as within
brain lesions visualized in MRI scans.

Curtin said that infections by other current viruses such as
Epstein-Barr virus -- which has also been linked with MS -- may trigger
expression of MSRV-Env. Lab studies have shown that the protein is
capable of triggering cellular events consistent with MS pathology such
as cytokine release, inhibition of nerve myelination, and expression of
intercellular adhesion molecules at the blood-brain barrier.

His firm has developed a monoclonal antibody targeting this
protein, and Curtin reported early results from a phase IIa clinical
study.

So far, 10 patients have been dosed with the agent, he said.
Single doses at 2 or 6 mg/kg have been administered to five patients
each.

In the low-dose group, four showed no change in MRI lesions 4
weeks after dosing compared with baseline, with one patient showing a
decrease. One patient with primary progressive MS had a "decrease of
inflammation," Curtin said.

Only four patients in the high-dose group had their 4-week MRI
scans when Curtin finalized his presentation, with all four showing
stable lesions.

A total of 16 adverse events were noted in the 10 patients,
ranging from neurological symptoms such as tremor and limb spasticity
to bradycardia, tachycardia, and bladder infection.

Patients in the trial are now receiving additional doses and
the firm expects to have final 6-month results from the study in
September.

Session co-moderator Anthony Reder, MD, of the University of
Chicago, commented that numerous viral theories of MS have been
suggested but proof has been elusive.

Nevertheless, he said, the effectiveness of interferon-beta as
an MS treatment is a hint that something viral is involved in the
disease. Interferons are a leading component of antiviral host-defense
mechanisms in humans and many other organisms, and are actually thought
to predate the dinosaurs.

Thus, Reder suggested, the notion that a fossilized retrovirus
could play a role in MS is not far-fetched.

On the other hand, Edward Fox told MedPage Today
that he has seen too many novel theories of MS fail in clinical-trial
tests to get excited about MSRV-Env at this point.

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